Autoimmune, respiratory and inflammatory diseases such as chronic obstructive pulmonary disorder (COPD) and asthma are chronic and often progressive diseases associated with a dysregulated or overactive immune system.
Asthma is the most common chronic disease among children and also affects millions of adults. Some 235 million people worldwide suffer from this disease.
COPD is a highly prevalent condition and a major cause of morbidity and mortality worldwide. As the disease progresses, patients with COPD may become prone to frequent exacerbations resulting in patient anxiety, worsening health status, lung function decline and increase in mortality rate. These episodes of worsening respiratory function lead to increases in health care utilization, hospital admissions and costs. Worse, frequent exacerbations are associated with a faster decline in lung function, thereby shortening life expectancy.
In addition to COPD and Asthma, other allergic and/or inflammatory disorders of lung include diseases such as Cystic Fibrosis and Idiopathic pulmonary fibrosis (IPF).
According to the recommendations of Global Initiative for Chronic Obstructive Lung Disease (GOLD), the first line therapy for COPD are long acting β-agonists, long acting muscarinic antagonist and inhalation corticosteroids. However, these drugs reduce the symptoms and exacerbations associated with the disease rather than targeting its molecular and cellular basis. Accordingly, there is still a need for further improvement in COPD therapy.
Roflumilast (Daliresp®), a PDE4 inhibitor, is approved as an oral therapy in the U.S. to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
In April 2010, the Pulmonary-Allergy Drugs Advisory Committee (PADAC) to the FDA voted 10 to 5 against approving roflumilast due to modest benefit and potential for adverse events. In March 2011, the FDA approved roflumilast with a narrower indication than had originally been pursued (namely, the treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations). Roflumilast has been reported to have dose dependent toxicity, which limits the use of roflumilast at higher doses. The table below shows adverse events (AEs) that occurred in at least 2% of those receiving roflumilast and greater than placebo.
AEsRoflumilast (n = 4438)Placebo (n = 4192)Diarrhoea420 (9.5)113 (2.7) Weight loss331 (7.5)89 (2.1)Nausea209 (4.7)60 (1.4)Headache195 (4.4)87 (2.1)Back pain142 (3.2)92 (2.2)Influenza124 (2.8)112 (2.7) Insomnia105 (2.4)41 (1.0)Dizziness 92 (2.1)45 (1.1)Decreased appetite 91 (2.1)15 (0.4)Data obtained from the FDA label for Dalresp ® (roflumilast) Aug. 13, 2013
R. W. Chapman et al., European Journal of Pharmacology, 571, 215-221 (2007), report experiments involving administration of roflumilast by inhalation to Brown Norway rats in an attempt to improve its therapeutic index.
According to the label for Daliresp, roflumilast N-oxide is an active metabolite of roflumilast. International Publication Nos. WO 2001/90076 and WO 2011/163469, both of which are hereby incorporated by reference, disclose the preparation and certain uses of roflumilast N-oxide. Additional efficacy, preclinical and clinical information for roflumilast and roflumilast N-oxide is provided in A. Hatzelmann et al., Journal of Pharmacology and Experimental Therapeutics, 297, 267-279, 2001; Center For Drug Evaluation And Research Pharmacology Review(s) on Roflumilast (Application Number: 022522Orig1s000) available online on the U.S. FDA website; D. S. Bundschuh et al., Journal of Pharmacology and Experimental Therapeutics, 297, 280-290, 2001; Rabe et al., Br. J. Pharmacol., 16353-67, 2011; Zuzana Diamant et al., Pulmonary Pharmacology & Therapeutics 24, 4 (2011) 353; and S. Vollert et al., Diabetologia, 55, 2779-2788, 2012, each of which is hereby incorporated by reference.
Despite currently available intervention therapies, respiratory disorders such as asthma and COPD remain a disease class with a significant unmet medical need. More effective therapies with fewer adverse events are needed.